Patrik Lassus

Cyclooxygenase-2 in Human Perinatal Lung

Cyclooxygenases-1 and -2 are the key enzymes in the conversion of arachidonic acid to prostanoids. Cyclooxygenase-2 (COX-2) takes part both in inflammation and in control of cell growth. COX-2 immunohistochemistry was performed on lung tissues from autopsies, with four groups included: fetuses (n = 4, GA = 16.0 to 32.0 wk), preterm infants (n = 10, GA = 23.0 to 29.9 wk), term infants (n = 6, GA = 38.7 to 42.0 wk), and infants with bronchopulmonary dysplasia (BPD) (n = 4, GA = 28.9 to 30.7 wk). COX-2 staining occurred exclusively in the epithelial cells resembling type II pneumocytes in the alveolae, and in ciliated epithelial cells in the bronchi. In fetuses, moderate intensity alveolar staining was seen in 90–100% cells lining the alveolar epithelium. In preterm infants, high intensity alveolar staining was seen in a scattered pattern. In term infants, the alveolar staining was also scattered, but with a lower proportion of positive cells. In BPD no staining appeared in alveolar epithelial cells. The most intense bronchial staining was found in fetuses and the least intense in term infants; staining was also seen in BPD. COX-2 is present in human perinatal lung from the gestational age of 16 wk, in a changing pattern. We suggest that COX-2 may, in addition to participating in inflammation, also play a developmental role in the perinatal lung.

Clara-cell secretory protein in preterm infants' tracheal aspirates correlates with maturity and increases in infection.

Clara‐cell secretory protein (CCSP), produced primarily by Clara cells in the conducting airways, is the most abundant soluble protein in pulmonary lavage fluid. CCSP is thought to be an immunosuppressive or anti‐inflammatory protein with protective functions in the respiratory tract against exaggerated inflammatory reactions. CCSP was measured in 98 tracheoalveolar fluid (TAF) samples from 24 preterm infants (gestational age, 27.9 ± 2.3 weeks, birth weight 1,020 ± 305 g) with respiratory distress syndrome during the first 2 postnatal weeks. The ratio of urea‐N in serum and in TAF was used to correct for dilution of TAF samples.

Lower concentration of pulmonary hepatocyte growth factor is associated with more severe lung disease in preterm infants

OBJECTIVES Hepatocyte growth factor (HGF) participates in normal lung development and in regeneration after lung injury in animals. We studied the role of HGF during the perinatal period and in the development of bronchopulmonary dysplasia (BPD). STUDY DESIGN HGF was measured in 172 tracheal aspirate fluid samples (TAF) from 17 preterm infants in whom BPD subsequently developed (gestational age, 27.2+/-1.7 weeks; body weight, 828+/-210 g) and from 15 who survived without BPD (gestational age, 26.8+/-1.9 weeks; body weight, 994+/-265 g) during the first 2 postnatal weeks. RESULTS Infants with subsequent development of BPD had lower HGF in TAF (45+/-9 pg/mL per IgA-sc) than those surviving without BPD (102+/-32 pg/mL per IgA-sc; P=.028). Lower HGF in TAF were seen in infants with more severe acute respiratory distress as defined as requirement for surfactant therapy (50+/-14 vs 146+/-50 pg/mL per IgA-sc in infants requiring no surfactant; P=.0001), for higher number of surfactant doses (r=-0.16, P=.06), and for mechanical ventilation >1 week (167+/-51 vs 51+/-14 pg/mL per IgA-sc in infants intubated <1 week; P=.0012). CONCLUSIONS These data show an association between lower HGF concentration in TAF and more severe lung disease in human preterm infants in the early neonatal period.

Endostatin Concentration in Cord Plasma Predicts the Development of Bronchopulmonary Dysplasia in Very Low Birth Weight Infants

INTRODUCTION. Endostatin is an antiangiogenic growth factor. Together with proangiogenic growth factors it acts to shape the developing vasculature. Dysregulation of angiogenesis is a component in the pathogenesis of bronchopulmonary dysplasia. OBJECTIVE. Our goal was to study whether the concentration of circulating endostatin at birth is associated with the development of bronchopulmonary dysplasia in very low birth weight infants. PATIENTS AND METHODS. Endostatin concentration was measured in cord plasma from 92 very low birth weight infants (gestational age < 32 weeks; birth weight < 1500 g) and 48 healthy term infants (gestational age > 37 weeks; birth weight > 2500 g). RESULTS. Endostatin concentration in very low birth weight infants was lower than in healthy term infants. Within the very low birth weight group no correlation existed between endostatin concentration and gestational age or relative birth weight. Very low birth weight infants who subsequently developed bronchopulmonary dysplasia had higher cord endostatin than those who did not. Higher endostatin concentration was associated with higher odds for bronchopulmonary dysplasia. Adjusted for gestational age, the odds for bronchopulmonary dysplasia were higher. CONCLUSIONS. Circulating endostatin in term infants was higher than in very low birth weight infants, suggesting a temporal pattern for fetal endostatin concentration. In very low birth weight infants a high concentration of circulating endostatin at birth is associated with the subsequent development of bronchopulmonary dysplasia.

Vascular endothelial growth factor and angiogenin levels during fetal development and in maternal diabetes.

We evaluated the concentrations of vascular endothelial growth factor (VEGF) and angiogenin in the umbilical cord blood from 14 fetuses with erythroblastosis or alloimmune thrombocytopenia and at birth from 28 preterm fetuses, from 42 healthy term fetuses, and from 24 term fetuses born to mothers with insulin-treated diabetes. A correlation appeared between VEGF and angiogenin levels (r = 0.44, p = 0.038). The gestational age correlated with both VEGF (r = 0.38, p = 0.0008) and angiogenin levels (r = 0.80, p = 0.0001). The concentration of VEGF was lower in fetuses born to mothers with insulin-treated diabetes than in the healthy term fetuses (p = 0.0028), but this difference was absent for angiogenin (p > 0.05). In conclusion, in umbilical cord plasma, a developmental increase was evident in concentrations of VEGF and angiogenin during the last trimester of gestation. That the umbilical cord VEGF level was lower in term fetuses born to mothers with diabetes than in term fetuses of healthy mothers may be associated with an aberrant fetal vascular development in diabetic pregnancies.

Placental Growth Factor and Vascular Endothelial Growth Factor Receptor-2 in Human Lung Development

OBJECTIVE. We examined the pulmonary expression of 2 proangiogenic factors, namely, placental growth factor and vascular endothelial growth factor receptor-2, during lung development and acute and chronic lung injury in newborn infants. METHODS. Six groups were included in an immunohistochemical study of placental growth factor and vascular endothelial growth factor receptor-2, that is, 9 fetuses, 4 preterm and 8 term infants without lung injury who died soon after birth, 5 preterm infants with respiratory distress syndrome of <2 days and 7 with respiratory distress syndrome of >10 days, and 6 with bronchopulmonary dysplasia. Placental growth factor concentrations in tracheal aspirate fluid were measured in 70 samples from 20 preterm infants during the first postnatal week. RESULTS. In immunohistochemical analyses, placental growth factor staining was seen in bronchial epithelium and macrophages in all groups. Distal airway epithelium positivity was observed mostly in fetuses and in preterm infants who died soon after birth. Vascular endothelial growth factor receptor-2 staining was seen in vascular endothelium in all groups and also in lymphatic endothelium in fetuses. Vascular endothelial growth factor receptor-2 staining in arterial endothelium was associated with higher and staining in venous endothelium with lower gestational age. In capillaries, less vascular endothelial growth factor receptor-2 staining was seen in bronchopulmonary dysplasia. The mean placental growth factor protein concentration in tracheal aspirate fluid during the first postnatal week was 0.64 ± 0.42 pg/mL per IgA-secretory component unit. Concentrations during the first postnatal week were stable. Lower placental growth factor concentrations correlated with chorioamnionitis and lactosyl ceramide positivity. CONCLUSIONS. The vascular endothelial growth factor receptor-2 staining pattern seems to reflect ongoing differentiation and activity of different endothelia. Lower vascular endothelial growth factor receptor-2 expression in capillary endothelium in bronchopulmonary dysplasia might be a reflection of the dysregulation of vascular development that is characteristic of bronchopulmonary dysplasia.

Pulmonary Endostatin Perinatally and in Lung Injury of the Newborn Infant

OBJECTIVE. Endostatin is a potent angiogenesis inhibitor. Angiogenesis is central for the development of the human lung. The role of endostatin in the development of the human lung and its connection to chronic lung disease remain unclear. We set out to study the role of endostatin in the developing human lung and in acute and chronic lung injury in the preterm infant. METHODS. Nine fetuses, 14 control neonates without primary lung disease, 14 preterm infants with respiratory distress syndrome, and 8 infants with bronchopulmonary dysplasia were included in the immunohistochemistry study. Tracheal aspirate-fluid samples of intubated very low birth weight infants during postnatal weeks 1 through 5 were analyzed with enzyme-linked immunosorbent assay. RESULTS. Endothelial cell staining was positive for endostatin in all 45 samples. Staining of epithelial cells (cuboidal, bronchiolar, and alveolar) was seen mostly in fetuses, as well as in infants with late respiratory distress syndrome and bronchopulmonary dysplasia. Staining in alveolar macrophages was most abundant in infants with late respiratory distress syndrome and bronchopulmonary dysplasia. Endostatin was expressed consistently in tracheal aspirate fluid, being highest during the first postnatal day. Higher endostatin concentrations correlated with parameters reflecting lower lung maturity. CONCLUSIONS. The pattern of pulmonary endostatin protein expression in immunohistochemistry and consistent endostatin protein appearance in tracheal aspirate fluid in human preterm infants indicate a role in the physiologic development of the lung. Preterm birth influences pulmonary endostatin protein expression, which may alter normal lung development and response to lung injury.

Cyclooxygenase-2 expression in primary Merkel cell carcinoma

Background:  Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine skin tumor. The typical course of MCC is rapid progression of the primary tumor and metastatic dissemination to the regional lymph nodes. Thus far, no biological, prognostic marker has been established for this aggressive neoplasm.

Consistent expression of HGF and c-met in the perinatal lung

Background: Hepatocyte growth factor (HGF), an epithelial cell mitogen, has been shown to participate in normal lung development and in regeneration after lung injury. In human preterm infants, lower pulmonary HGF has been associated with more severe respiratory disease. Objectives: We studied the protein expression of HGF and its receptor c-met during the perinatal period in the human lung. Methods: Immunohistochemistry for HGF and c-met was performed on lung tissues from autopsies of 4 fetuses, 5 preterm infants, 5 term infants, and 4 infants with bronchopulmonary dysplasia. Results: Immunohistochemistry for HGF showed staining in all cases in mesenchymal cells (fibroblasts and cartilage cells). Additional staining was found in bronchial and distal airway epithelium. Immunohistochemistry for c-met showed staining in bronchial and distal airway epithelium, and in most cases in neutrophils. Conclusions: The consistent expression of HGF and c-met during the perinatal period supports a physiological role for HGF in human lung development.

The free scapular flap with latissimus muscle reduces fistulas in mandibular reconstruction

INTRODUCTION The free scapular chimeric flap is a less common choice for facial reconstruction. This study aimed to evaluate the versatility and safety of the flap, the procedure for a two-team approach, the safety of the osteotomies, the possibility of dental implants and donor-site sequelae and complications. PATIENT AND METHODS We analysed 34 consecutive patients with oral cancer undergoing large resections in the maxillofacial region as well as scapular chimeric free flap reconstruction. We performed 26 mandibular, six maxillary and two orbital reconstructions using a two-team approach, mainly without repositioning the patient. RESULTS No flaps were lost. Three patients with a scapular bone and fasciocutaneous flap developed a post-operative fistula, whereas no fistulas developed when the flaps included a muscular component. All osteotomies showed confirmed osseal consolidation. Seven patients received a total of 23 dental implants for oral rehabilitation; no implants were lost. CONCLUSIONS The scapular flap is reliable and contains sufficient bone to tolerate both multiple osteotomies and osseointegrated dental implants. The flap can be harvested in a slightly tilted decubital position, thus shortening the theatre time. The use of a separate muscle around the scapular bone in mandibular reconstruction is associated with a lower risk of oral fistulas.